Donor/acceptor-substituted rhodium carbenoids such as 1 have been shown to be versatile intermediates in organic synthesis. These carbenoids are capable of extremely selective reactions, and when catalyzed by rhodium prolinates such as Rh2(S-DOSP)4 (2) the reactions are routinely highly enantioselective.


One of the earliest explored reactions was the cyclopropanation chemistry of the donor/acceptor-substituted carbenoids. As illustrated in the reaction of the vinyldiazoacetate 3 with styrene, the reactions are highly diastereoselective, which is in marked contrast to the typical cyclopropanation chemistry of ethyl diazoacetate. The Rh2(S-DOSP)4 catalyzed reaction of 3 with styrene at −78° C. generates the cyclopropane 4 in 98% de and 98% ee.
The reaction conditions have been recently optimized such that the cyclopropanations can be conducted with immobilized catalysts or with catalyst loadings as low as 0.001%. The optimum catalyst for the high turnover work was the bridged catalyst Rh2(S-biTISP)4.

A major breakthrough in the chemistry of the donor/acceptor-substituted carbenoids was the discovery that these carbenoids are very effective for selective intermolecular C—H insertions. This is a very powerful synthetic strategy for “C—H activation”, and it is arguably the most practical and versatile method to date for catalytic asymmetric C—H functionalization. Prior to our work, the intramolecular C—H insertions were well established but the intermolecular version was not considered synthetically useful because the conventional carbenoids were too reactive and very prone to dimerization. These problems have now been solved by using the donor/acceptor-substituted carbenoids because they are more stabilized than the conventional carbenoids.
The C—H functionalization strategy offers an alternative to many of the classic reactions of organic synthesis. It can be considered as a surrogate to the aldol reaction, the Claisen rearrangement, the Mannich reaction, and the Michael addition, and, in all cases, excellent control of both relative and absolute stereochemistry is possible. Furthermore, the chemistry has been used in the direct synthesis of pharmaceutical targets such as (+)-cetiedil (5), (+)-indatraline (6), threo-methylphenidate (Ritalin) (7), and the lignan α-conidendrin (8).



The C—H activation chemistry is capable of spectacular chemoselectivity. C—H functionalization is favored at sites that stabilize developing positive charge on the carbon undergoing insertion, but this effect is counterbalanced by the steric influence of the carbenoid.
In all of the studies described above, the electron withdrawing group was a methyl ester. Even increasing the size of the methyl ester to a tert-butyl ester caused a dramatic drop in the enantioselectivity (from 90% ee to 50% ee, 74% ee to 9% ee). Therefore, it would be highly desirable to develop a new type of chiral catalyst that would be applicable to other types of electron withdrawing groups. The present invention is directed, in part, to addressing this need.